Dipeptidyl peptidase IV (DPPIV) is a serine protease which specifically hydrolyzes dipeptide —X-Pro (X=arbitrary amino acid) from the free N terminus of a polypeptide chain.
Glucose-dependent, insulin secretion-stimulating hormones, known as incretins (GLP-1: Glucagon-Like Peptide-1 and GIP: Glucose-dependent Insulinotropic Polypeptide) secreted in the digestive tract following meals are rapidly hydrolyzed and inactivated by DPPIV. When the hydrolysis by DPPIV is suppressed, the action of incretin (GLP-1 an GIP) is enhanced, which in turn increases the glucose-stimulated secretion of insulin from the β cells of the pancreas. This has been shown to improve hyperglycemia in the oral glucose tolerance test (see Diabetologia 1999 November, 42(11), 1324-31). In addition, GLP-1 is known to be involved in the suppression of appetite and food intake. GLP-1 has also been reported to have the effect of protecting the β cells of the pancreas by enhancing β cell differentiation and proliferation.
Thus, a DPPIV inhibitor can be a useful therapeutic or preventive agent for diseases with which GLP-1 and/or GIP are associated, such as obesity and diabetes mellitus.
Furthermore, there are many reports suggesting a relationship between dipeptidyl peptidase IV and various diseases as described below. Thus, a DPPIV inhibitor can be a therapeutic agent for diseases such as:
(1) preventive and therapeutic agents for AIDS (see Science 1993, 262, 2045-2050),
(2) preventive and therapeutic agents for osteoporosis (see Clinical chemistry 1988, 34, 2499-2501),
(3) preventive and therapeutic agents for intestinal disorders (see Endocrinology 2000, 141, 4013-4020),
(4) preventive and therapeutic agents for diabetes mellitus, obesity, and hyperlipidemia (see Diabetes 1998, 47, 1663-1670; and Life Sci 2000, 66(2), 91-103),
(5) preventive and therapeutic agents for angiogenesis (see Agents and Actions 1991, 32, 125-127),
(6) preventive and therapeutic agents for infertility (see International Publication WO 00/56296),
(7) preventive and therapeutic agents for inflammatory diseases, autoimmune diseases, and chronic rheumatoid arthritis (see The Journal of Immunology 2001, 166, 2041-2048), and
(8) preventive and therapeutic agents for cancer (see Br J Cancer 1999 March, 79(7-8), 1042-8; and J Androl 2000 March-April, 21(2), 220-6).
Some DPPIV inhibitors are disclosed in the Publication of US patent No. 2002/0161001; International Publication WO 03/004496; and Publication of US patent No. 2002/0198205. However, there is no known DPPIV inhibitor having a hypoxanthine or imidazopyridazinone structure backbone.
A compound having DPPIV-inhibiting activity that can be used as a pharmaceutical agent is being anxiously sought as described above. However, a compound with excellent DPPIV-inhibiting activity, which is also highly useful as a clinically effective pharmaceutical is yet to be discovered. Specifically, an objective of the present invention is to provide compounds having DPPIV-inhibiting activity, which can be used as preventive, therapeutic, or alleviating agents for diabetes mellitus or such diseases.